Developmental dysfunction in a preclinical model of Kcnq2 developmental and epileptic encephalopathy
Background: Developmental and epileptic encephalopathies (DEE) are rare but severe neurodevelopmental disorders characterised by early-onset seizures often combined with developmental delay, behavioural and cognitive deficits. Treatment for DEEs is currently limited to seizure control and provides n...
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Elsevier
2025-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S096999612400384X |
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| author | Miaomiao Mao Nikola Jancovski Yafit Kushner Lucas Teasdale Phan Truong Kun Zhou Samuel Reid Linghan Jia Ye Htet Aung Melody Li Christopher A. Reid Sean Byars Ingrid Scheffer Steven Petrou Snezana Maljevic |
| author_facet | Miaomiao Mao Nikola Jancovski Yafit Kushner Lucas Teasdale Phan Truong Kun Zhou Samuel Reid Linghan Jia Ye Htet Aung Melody Li Christopher A. Reid Sean Byars Ingrid Scheffer Steven Petrou Snezana Maljevic |
| author_sort | Miaomiao Mao |
| collection | DOAJ |
| description | Background: Developmental and epileptic encephalopathies (DEE) are rare but severe neurodevelopmental disorders characterised by early-onset seizures often combined with developmental delay, behavioural and cognitive deficits. Treatment for DEEs is currently limited to seizure control and provides no benefits to the patients' developmental and cognitive outcomes. Genetic variants are the most common cause of DEE with KCNQ2 being one of the most frequently identified disease-causing genes. KCNQ2 encodes a voltage-gated potassium channel KV7.2 widely expressed in the central nervous system and critically involved in the regulation of neuronal excitability. In this study, we aimed to characterise a KCNQ2 variant (K556E) found in a female patient with DEE using a heterologous expression system and a knock-in mouse model. Methods: Wild-type KCNQ2 or K556E variant were expressed in Chinese Hamster Ovary (CHO) cells (with or without KCNQ3) and their biophysical properties assessed using patch clamp recordings. We further engineered a new Kcnq2 DEE mouse model (K557E) based on the K556E variant and characterised it using behavioural, electrophysiological, and transcriptome analysis. Results: A mild loss of function was observed only when the mutant channel was co-expressed with KCNQ3 in the heterologous system. The heterozygous knock-in mice showed a reduced survival rate and increased susceptibility to induced seizures. Electrophysiology recordings in brain slices revealed a hyperexcitable phenotype for cortical layer 2/3 pyramidal neurons with retigabine (KV7 channel opener) able to rescue both the increased sensitivity to chemically-induced seizures in vivo and neuronal excitability ex vivo. Whole-brain RNA sequencing revealed numerous differentially expressed genes and biological pathways pointing at dysregulation of early developmental processes. Conclusions: Our study reports on a novel Kcnq2 DEE mouse model recapitulating aspects of the disease phenotype with the electrophysiological and transcriptome analysis providing insights into KCNQ2 DEE mechanisms that can be leveraged for future therapy development. |
| format | Article |
| id | doaj-art-9703503596414bd9b4f6cf7e6d4ccb36 |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-9703503596414bd9b4f6cf7e6d4ccb362025-01-24T04:44:39ZengElsevierNeurobiology of Disease1095-953X2025-02-01205106782Developmental dysfunction in a preclinical model of Kcnq2 developmental and epileptic encephalopathyMiaomiao Mao0Nikola Jancovski1Yafit Kushner2Lucas Teasdale3Phan Truong4Kun Zhou5Samuel Reid6Linghan Jia7Ye Htet Aung8Melody Li9Christopher A. Reid10Sean Byars11Ingrid Scheffer12Steven Petrou13Snezana Maljevic14The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, AustraliaThe Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, AustraliaThe Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, AustraliaThe Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, AustraliaThe Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, AustraliaThe Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, AustraliaThe Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, AustraliaThe Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, AustraliaThe Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, AustraliaThe Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, AustraliaThe Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, AustraliaThe Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, AustraliaEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria 3084, AustraliaThe Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, Australia; Praxis Precision Medicine Inc, Cambridge, MA 02142, USA; Corresponding authors at: 30 Royal Parade, Parkville, Victoria 3052, Australia.The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, Australia; Corresponding authors at: 30 Royal Parade, Parkville, Victoria 3052, Australia.Background: Developmental and epileptic encephalopathies (DEE) are rare but severe neurodevelopmental disorders characterised by early-onset seizures often combined with developmental delay, behavioural and cognitive deficits. Treatment for DEEs is currently limited to seizure control and provides no benefits to the patients' developmental and cognitive outcomes. Genetic variants are the most common cause of DEE with KCNQ2 being one of the most frequently identified disease-causing genes. KCNQ2 encodes a voltage-gated potassium channel KV7.2 widely expressed in the central nervous system and critically involved in the regulation of neuronal excitability. In this study, we aimed to characterise a KCNQ2 variant (K556E) found in a female patient with DEE using a heterologous expression system and a knock-in mouse model. Methods: Wild-type KCNQ2 or K556E variant were expressed in Chinese Hamster Ovary (CHO) cells (with or without KCNQ3) and their biophysical properties assessed using patch clamp recordings. We further engineered a new Kcnq2 DEE mouse model (K557E) based on the K556E variant and characterised it using behavioural, electrophysiological, and transcriptome analysis. Results: A mild loss of function was observed only when the mutant channel was co-expressed with KCNQ3 in the heterologous system. The heterozygous knock-in mice showed a reduced survival rate and increased susceptibility to induced seizures. Electrophysiology recordings in brain slices revealed a hyperexcitable phenotype for cortical layer 2/3 pyramidal neurons with retigabine (KV7 channel opener) able to rescue both the increased sensitivity to chemically-induced seizures in vivo and neuronal excitability ex vivo. Whole-brain RNA sequencing revealed numerous differentially expressed genes and biological pathways pointing at dysregulation of early developmental processes. Conclusions: Our study reports on a novel Kcnq2 DEE mouse model recapitulating aspects of the disease phenotype with the electrophysiological and transcriptome analysis providing insights into KCNQ2 DEE mechanisms that can be leveraged for future therapy development.http://www.sciencedirect.com/science/article/pii/S096999612400384XM-channelsGenetic epilepsyMouse modelNeuronal excitabilityDevelopmental dysfunction |
| spellingShingle | Miaomiao Mao Nikola Jancovski Yafit Kushner Lucas Teasdale Phan Truong Kun Zhou Samuel Reid Linghan Jia Ye Htet Aung Melody Li Christopher A. Reid Sean Byars Ingrid Scheffer Steven Petrou Snezana Maljevic Developmental dysfunction in a preclinical model of Kcnq2 developmental and epileptic encephalopathy Neurobiology of Disease M-channels Genetic epilepsy Mouse model Neuronal excitability Developmental dysfunction |
| title | Developmental dysfunction in a preclinical model of Kcnq2 developmental and epileptic encephalopathy |
| title_full | Developmental dysfunction in a preclinical model of Kcnq2 developmental and epileptic encephalopathy |
| title_fullStr | Developmental dysfunction in a preclinical model of Kcnq2 developmental and epileptic encephalopathy |
| title_full_unstemmed | Developmental dysfunction in a preclinical model of Kcnq2 developmental and epileptic encephalopathy |
| title_short | Developmental dysfunction in a preclinical model of Kcnq2 developmental and epileptic encephalopathy |
| title_sort | developmental dysfunction in a preclinical model of kcnq2 developmental and epileptic encephalopathy |
| topic | M-channels Genetic epilepsy Mouse model Neuronal excitability Developmental dysfunction |
| url | http://www.sciencedirect.com/science/article/pii/S096999612400384X |
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